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The Man-made H5N1 Controversy Heats Up: What Next? (Part Four)

Yesterday 21 scientists and 1 ethicist concluded their two-day WHO meeting on the fate of man-made flu viruses. Describing the meeting late Friday night from Geneva WHO Assistant Director Keiji Fukuda repeatedly used the words "heated" "hot" and "complicated". Decisions were reached, however, and they are odd. Basically all research involving genetic manipulation of H5N1 avian flu viruses, and publication of research on super-transmissible strains is on an indefinite moratorium. A decision will be reached (by somebody, unstated) to lift both moratoriae when it is deemed that the general public worldwide has been educated to accept such research "without anxiety," Fukuda said.

Part of gaining public acceptance of such scientific research will be convening more meetings, with a broader representation of civil society and the professions outside of science. The following blog was written well before the meeting convened, and this decision was reached.

This is the third of a daily series of blog postings over the next week that will dwell on issues surrounding the H5N1 controversy.

Today we address: The Danger of an Overly Narrow Debate

Presumably the National Scientific Advisory Board on Biosecurity (NSABB), NIH, WHO, and other scientific institutions will create policy guidelines aimed at resolving tensions between public health and biosecurity. As contentious as debates among scientists regarding H5N1 are, finding common ground for flu research will prove easier than determining the ramifications for science, more broadly. All parties will, therefore, prefer a very narrow discussion and policy prescriptions.

This is dangerous.

Like high court legal decisions, major moments akin to this one in the history of science have tended to set precedents that were followed for decades. The debate may focus on Fouchier’s H5N1 experiment, but decisions regarding bio-safety, censorship, sharing or storing of the manmade viruses, and advance screening of H5N1 research hereon will be cited for years to come as other controversies arise. And they will arise because we are at the front end of a spectacular revolution in biology that will in a few years render the wholesale manufacture of life forms, from the “bottom up,” or DNA and RNA to whole organism, a routine exercise. If a comfort zone is found for H5N1, alone, it may allow or forbid important experiments and security procedures for other types of biology research.

modifying naturally occurring genomes to allow these modified genomes to function in new contexts or to create entirely novel organisms…Although the term ‘synthetic biology’ has been used in various ways, it is generally understood to describe research that combines biology with the principles of engineering to design, construct, or adapt existing DNA, or other biological structures into standardized, interchangeable, building blocks for use in creating genetic systems that carry out desired functions.

This is the norm in biology today, not a rare or renegade movement. Routinely researchers create libraries of natural and manmade genetic sequences that are known to be associated with given traits, and jigger them about much as an engineer 100 years ago might manipulate thousands of different screws, bolts, nuts, wires and plates of steel to create a machine. Cells or microorganisms can be stripped of their natural genetic material, and “transplanted” with the full genome of an entirely different species. Traits associated with one life form can be transplanted to another. A bacterium, for example, that is a beneficial for human digestion and therefore not likely to stimulate human immune response can be stripped of its native DNA, and filled with, perhaps, the DNA of anthrax, or Clostridium botulinum. None of this is science fiction.

Indeed, the IOM spent a fair amount of time debating whether synthetic biology constitutes a new twenty-first century form of Darwinian evolution, as it is now apparent that so-manipulated organisms can reproduce, adapt, and therefore “evolve” quickly in the laboratory.

Fouchier’s ferret experiments were old-fashioned biology, because he promoted H5N1 evolution roughly the same way Luther Burbank selected for plants in his gardens, or Joshua Lederberg forced antibiotic resistance in 1950s bacterial research. In essence, he increased natural selection pressure and let the virus do its thing in response.

Now that Fouchier has shown such a nasty, super-lethal, and super-transmissible form of the virus can be made through the crude process, publication of the genetic sequence of his “super-flu” is all a good synthetic biologist needs to make the hideous organism. It would be frankly a waste for an evil-doer to copy Fouchier’s crude techniques to manufacture super-flu. Synthetic biology offers far easier, cheaper, and more controlled possibilities, without the fuss and bother of maintaining animal colonies. Moreover, bottom-up construction of the super-flu obviates many laboratory safety measures, as the greatest safety risks for the Rotterdam scientists were undoubtedly related to the infected ferrets; their sneezes, bites, claws, and airborne environs.

To date, the strife surrounding H5N1 has been argued almost exclusively by virologists and bioterrorism experts, and even the virus expertise is narrowly drawn from the ranks of “influenza-ologists.” A wise biosecurity debate would feature the likes of Gerald Joyce, a Scripps Institute synthetic biologist; synthetic cell-makers from the J. Craig Venter Institute; biohackers and DIY advocates from such places as iGEM andBioBricks; biosensor expert Christopher French from the University of Edinburgh; synthetic immune system experimenter Stephen Johnson of Arizona State University; DNA librarian George Church of Harvard; genetic “mix and matcher” Christopher Voigt of MIT.

A Harvard team led by Shawn Douglas has created nano-robots made of twisted DNA, inside of which can be placed molecules, such as drugs. The nano-DNA-robots bypass the human immune system and readily enter cells, carrying their cargo inside. Still at the frontier end of development, the technique offers the possibility of Trojan Horse inserting desired chemicals into specific cell types, altering their behaviors, perhaps killing them. For example, the approach could theoretically be used to deliver chemotherapy poisons exclusively to tumor cells, minimizing the collateral damage typically caused to patients’ entire bodies when undergoing treatment. Equally theoretically possible would be use of nano-robots to deliver biotoxins for malevolent reasons.

In January, researchers from Michigan State University forced evolution of a new virus in their laboratory.Richard Lenski and his team did not use synthetic biology methods to push Lambda virus evolution, but rapidly sequenced the virus. They showed that under modest selection pressure the virus, which is harmless to humans, underwent four nucleotide mutations that gave it the ability to infect bacteria through an entirely novel method. Lenski noted that the methods used in the lab mimic evolutionary pressure in nature, and the dangerous jump Lambda made occurred so rapidly (in two weeks) that he initially thought an error had been made and repeated the entire experiment. Lenski was the first to note that his four-mutation Lambda findings have implications for assessing the probability that H5N1 will naturally undergo its five-nucleotide change to become Fouchier’s killer virus. The experiment demonstrated that viruses can undergo multiple-site mutation naturally, and quite suddenly – which makes the concept of a five-mutation change in H5N1 seem less improbable.

Influenza experts demonstrate high hubris when they extrapolate solely from flu work to predict events in nature. A far broader range of microbial evolution expertise would bring intellectual rigor and authenticity to the forecasting, both of which are now woefully absent.

Missing from the formal debate, though some have contributed to the tsunami of recent publication, are ethicists and international legal experts. Ruth R. Faden and Ruth A. Karron of Johns Hopkins School of Medicine have laid out ethical principles that have been ignored, both in the narrow H5N1 discussion and broader dual use contention. On the legal side Georgetown’s Lawrence Gostin has offered some insights, but it would be wise to draw University of Indiana’s International Health Regulations expert David Fidler formally into the fray, along with counterparts from outside the U.S.

But this is not so with H5N1. Humans might not want to lose their chickens, but they are not really that bothered about a few million dead birds. It is the possibility of mammalian transmission that really grabs people's attention. And yet the scientific community has not really engaged in the debate—perhaps because to do so would have risked an Asilomar-like moratorium on the important work of understanding influenza transmission. But such a discussion does seem worthwhile as a way of clarifying which research should be funded in the first place rather than how the results should be disseminated after the fact.

Avoiding researcher-led debates on the potentials of dual-use science resulted, at least on some occasions, in politically led debates on the same subjects. That road led to President George W. Bush's ban on embryonic stem cells and the European Union's moratorium on genetically engineered crops. Let's hope the debate on influenza transmission follows a more rational path.